1790
VOl. 50
J. A. ARVIN AND ROGER ADAMS
[CONTRIBUTION
FROM THE
DEPARTMENT OF CHEMISTRY, UNIVERSITY OF ILLINOIS]
A’-CYCLOPENTENYLETHYL ALKYL ACETIC ACIDS AND THEIR BACTERICIDAL ACTION TOWARD B. LEPRAE. XII.1 BY J. A. ARVIN AND ROGERADAM$ RECEIVEDAPRIL 7, 1928
PUBLISHED JUNE 5, 1928
The fact that a A2-cyclopentenyl group is present in chaulmoogric and hydnocarpic acids warrants a more extended investigation of synthetic acids containing this grouping than is described in an earlier paper. A complete series of A2-cyclopentenylethyl alkyl acetic acids (I), where “R” varies from n-hexyl t o n-lauryl, was prepared. This series was selected partly because of the comparative ease of preparation and partly because of the fact that i t would probably be a more effective series than the A2-cyclopentenylalkyl acetic acids, judging from the greater effectiveness of cyclohexylethyl alkyl acetic acids over the cyclohexyl alkyl acetic acids. A few members of the A2-cyclopentenyl alkyl acetic series (11) where the “R” group is decyl, undecyl and lauryl were also made, since in the earlier investigation not a sufficient number of members of the series were prepared in order to show where the maximum action might be found. C H CH I-CH-(CH~),CH(CO~H)R -/ CHz CHa
CH CH
I-YCH-CH / (CO,H)R
CHz CHz
I I1 I n Tables I and I1 are given the bacteriological results on these compounds. The most effective substances in Table I are those containing 16 t o 19 carbon atoms in the molecule, as found for other acids previously described, and the degree of bactericidal action appears to be approximately the same as of those substances of essentially the same molecular weight found in other series. TABLEI A~-CYCLOPENTENYLETHYL ALKYL ACETIC ACIDS, CsH7(CH2)zCH(C0z€I)R R
25
CeH13 C7HlS CSH17 CgHie CioHz1 CllH23 -
-
ClZH25
-
36 -
_ -
50 %
-
-
-
Dilutions of Sodium Salts in Thousands 74 85 100 125 147
62
165
192
t
-
230
+ + + + + + - - * + - - - - - * - * * - - - - - - - - ++ - - * * * + + + + - + + + + + + + +
=
*
*
-
-
t
-
-
Paper XI in this series, Yohe and Adams, THISJOURNAL, 50, 1503 (1928). This communication is an abstract of a portion of a thesis submitted by J. A. Arvin in partial fulfilment of the requirements for the Degree of Doctor of Philosophy in Chemistry a t the University of Illinois. 1 2
June, 1923
SOME ALKYL ACETIC ACIDS AND B. LEPRAE.
XI1
1791
TABLEI1 A~-CYCLOPENTENYL ALKYL ACETIC ACIDS, C6H7CH(CO2H)R n-CloHr, n-CllH23 ?1-Cl2H2,
;Y = 3 5
- - - - * + + + + + + + * * + + + + + A 2 - C ~ ~ALKYL ~ ~ACETIC ~ f ACIDS, ~ TC~H7(CHz)zCOzH ~ ~ ~ ~ **+++++++ + + + + + + + + + -***+++++ + + + + t + + + +
- - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - =k -
+ + + + +
In Table I11 the maximum bactericidal action obtained with the most effective isomers in series analogous to those prepared in this investigation is given. TABLE I11 COMPARISON OF BACTERICIDAL EFFECTOF VARIOUSANALOGS Max. effective General Formula
1. C~H;(CH2)zCH(C0zH)R (cyclopentenyl)
2. CaH7CH(C0&)R (cyclopentenyl)
3. C6Hs(CH2)zCH(C@zH)R (cyclopentyl)
4.
CsHgCH(CO2H)R(cyclopentyl)
5. C6H11(CHz)2CH(C0zH)R (cyclohexyl)
6. CsH11CH(C02H)R(cyclohexyl)
R E
dilution in thousands
n-C7H16 85 n-CsH17 125 ?t-CsHis 147 n-CI0Hz1 192 n-CsHlg 150 n-CloHzl 170 ~ - C I ~ H Z ~120 n-C7Hl~ 160 n-CsHir 170 n-CgHle 111 n-CIoHzl 143 n-C11Hz3 153 n-C6H13 160 n-C7HI5 220 n-CsHir 320 n-C8H1? 111 n-CgHle 176 n-CloHzl 176 n-C11Hz3 153
Empirical formula
Cl6Hls@z C17H80OZ CdLzOz CleHsaOz C16H2802 C17H300z CisHszOz C16H3002 C17H3202 Cl6H3002 CiiHszOz CisHsaOz C16HaoOz C17H32OZ C18H3402 C16H3002 C17H3202 CisHa40z C18H3602
The differences between the bactericidal effects of compounds containing approximately the same number of carbon atoms is not significant enough to be worthy of discussion. It is of interest to note that by comparing series 1 and 2 with series 3 and 4 the olefin linkage has not produced any specific effect. The chief raw material used for the preparation of these compounds was cyclopentenyl chloride] which has been described in previous articles. The cyclopentenylethyl bromide was prepared by the reduction of ethyl cyclopentenyl acetate, prepared in turn by the esterification of the acid produced by the malonic ester synthesis from cyclopentenyl chloride.
1792
J. A. ARVIN AND ROGER ADAMS
VOl. 50
I n earlier work an attempt was made by C. R. Noller to synthesize d,l-hydnocarpic acid by the condensation of A2-cyclopentenylethyl magnesium bromide with methyl-s-aldehydo-octanoate and then elimination of the hydroxyl group. Before the work was entirely completed, the synthesis of d,Z-chaulmoogric acid by Perkins through a different procedure led to the abandonment of the former research. Preparation of methylS-hydroxy-d,Z-hydnocarpate and the corresponding acid had already been completed, so that the experimental results of Noller are described in this paper. CH CH /=)CH2CH2Br I-/ CHz CHz
+ CHO-(CH2);-C02CHa +
The bacteriological work was carried out by W. &I.Stanley.
Experimental A2-Cyclopentenyl Ethanol.-This was prepared as described by Noller and Adains.3 AWyclopentenyl Ethyl Bromide.-A solution of 62.5 g. of cyclopentenyl ethanol in 1.50 cc. of dry toluene was cooled t o - 5 " and a solution of 50 g. of redistilled phosphorus tribromide in 100 cc. of toluene was added slowly with shaking a t such a rate that the temperature did not rise above 0". After the addition of the tribromide, the mixture was allowed t o warm t o room temperature, stand for one-half hour and was then heated on a steam-cone for one hour. The mixture was cooled, decomposed by pouring it into cold water, separated and the upper layer washed with a 57, solution of sodium hydroxide and then with water. The bromide thus obtained, after careful fractionation, boils a t 71-72' a t 16 mm. About 158 g. of bromide was obtained from 190 g. of alcohol; n2,, 1.4995; d!', 1.2869. Anal. Calcd. for C7H11Br:Br, 45.71. Found: 47.48. AWyclopentenyl Butanol.-A2-Cyclopentenyl ethyl magnesium bromide was condensed with ethylene oxide according t o the procedure described by Hiers and Adams.' The average yield of the butanol was 38%; b. p. 118-123" a t 24 mm.; n2,, 1.4723; d:', 0.9317. Calcd. for CgH160: C, 77.09, H , 11.52. Found: C, 76.91; H, 11.62. As a by-product a substance boiling from 98-103 'at 24 mm. was obtained, the structure of which was not determined. AWyclopentenyl Butyl Bromide.-A2-Cyclopentenyl butanol was converted to the bromide in a manner similar t o the preparation of cyclopentenylethyl bromide from the corresponding alcohol. The product formed in 47"; yields; b. p . 82-86" a t 5 mm.; it2:, 1.4942; d:', 1.2229. Anal. Subs, 0.3370; 13.98 cc. of 0 1193 ,V AgNOa. Calcd. for CSHIIBr: Br, 39.35. Found: Br, 39.56. Diethyl A2-Cyclopentenyl Alkyl Malonate%-Diethyl A2-cyclopentenylethyl and diethyl A2-cyclopentenylbutyl malonates were prepared by the condensation of the corresponding bromides and malonic ester in the usual way; yields were about 6 6 4 9 % . a
Noller with Adams, THISJOURNAL, 48, 2444 (1926).
* Hiers with Adams, ibid., 48, 2385 (1926).
June, 1028
SOME ALKYL ACECTI ACIDS AND B. LEPRAE.
1793
XI1
A*-Cyclopentenylalkyl Malonic Acids.-The malonic acids of this series were prepared according to the procedure described by Adams, Stanley and Stearns.5 They were purified by recrystallization from benzene and were obtained in essentially quantitative yields. A*-Cyclopentenylethyl Acetic Acids and AWyclopentenylbutyl Acetic Acids.-These were prepared from the corresponding malonic acids by heating for a few hours at 150-155". Diethyl AWyclopentenyl and Diethyl A2-Cyclopentenylethyl Alkyl Malonates.-
TABLEI V DIETHYL A*-CYCLOPENTENYLETHYL ALKYL MALONATES, C6H;(CHz)2C(C02C2H5)zK R =
dr
:n
B. p . , O C .
~ - C B I I152-155 ~~ (2 mm.) ?z-CiHlb 159-162 (1.4 mm.) n-CsH1; 178-181 (2 mm.) ~z-CQH 176-180 ~ ~ ( 1 , 5 mm.) ~z-C~O 183-187 H ~ ~ (2.1 mm.) I Z - C ~ ~190-194 H ~ ~ ( 2 . 1 mm.) n-C12H25197-201 ( 2 , 2mm.)
1.4598 0,9742 1.4602 .9649 1.4605 ,9624 1.4609 ,9567 1.4613 .9531 1.4616 ,9486 1.4618 ,9460
Calcd., % C H
70.94 71.53 72.07 72.57 73.04 73.47 73.87
Found, % C H
10.13 10.30 10.46 10.60 10.73 10.86 10.98
70.90 7i.76 71.73 72.47 72.94 73.25 73.49
10.15 10.33 10.41 10.62 10.95 10.80 11.03
DIETHYL A 2 C ~ALKYL ~ MALONATES, ~ ~ ~ C~~ H ;~C ( C~O ~ C~Z H ~~) ~ R~ K = ~z-C~O 170-172 H ~ ~ ( 1 . 5 mm.) 1.4616 ,9642 72.07 10.46 72.20 10.40 ? I - C ~ ~176-180 H ~ ~ (1 mm.) 1.4622 .9598 72.57 10.60 72.24 10.52 tt-C12Hz6193-196 (2 mm.) 1.4627 ,9559 73.04 10.73 72.66 10.51 DIETHYL+A*-CYCLOPENTENYLALKYL MALONATES, C5H7(CH,),CH(CO2C~H&
x= 4
152-155 (3 mm.)
1.4598 1.0077
68.04
9.29
67.71
0.57
TABLEV K =
AWYCLOPENTENYLETHYL ALKYLACETICACIDS,CsHI(CH2)2CH(C02H)R n'," dy Calcd., % Found, % M. p., OC.
.
n-CaHI1 ... . ?z-C,Hlj . . . .. n-CsH17 .... .. , .. u-CQHlg I Z - C ~ ~ H. .~. .~. I I - C ~ , H ~. ~. . . . u-CIZH2a 30-31 . 5 I
B . p., ' C .
1GO-163 ( 2 . 3 mm.) 166-168 ( 2 . 2 m m . ) 174-176 (1.8mm.) 183-185 (2 mm.) 186-188 ( 1 . 5 m m . ) 190-193 ( 1 . 3 mm.) 199-203 (1 . 5 mm.)
1.4697 1.4698 1.4700 1.4701 1.4702 1.4703
0.9426 ,9358 ,9315 ,9269 .9227 ,9196
C
H
C
H
75.57 76.12 76.62 77.06 77.47 77.84 78.18
10.99 11.19 11.37 11.51 11.65 11.77 11.89
75.43 76.37 76.62 76.88 77.33 77.68 77.97
11.17 11.14 11.30 11.56 11.73 11 .?ti 11.82
AWYCLOPENTEXYLALKYLACGTICACIDS,CsHiCH(C02H)K K = I I - C I O H ~ ~. . . . . 183-186 (1.5mm.) 1.4692 ,9319 76.62 11.37 76.54 I Z - C ~ ~36-38 H~~ 188-190 (1.5 mm.) .... . . . 77.06 11.51 7 6 . 7 2 202-204 (2 mm.) ... . . . 77.47 11.65 77.07 N - C I ~ H ~38-39 K W - A*-CYCLOPENTENYLALKYL ACETIC ACIDS, CsH7(CH2),C02H X = 3 125-126 (4 mm.) 1.4718 ,9904 70.14 9.16 70.16 1.4740 ,9862 72.47 9.96 72.80 5 149-154 (5 mm.)
.
Adams, Stanley and Steams, THISJOURNAL, 50,1475 (1928)
11.22 11.39 11.83
9.52 10.14
7
~
1794
J. A. ARVI" AND ROGER ADAMS
Vol. 50
The diethyl A2-cyclopentenyl alkyl malonates were prepared from diethyl Aa-cyclopentenyl malonate and the proper alkyl bromide by the procedure described by Adams, Stanley and Stearns.6 The yields were 58-60010. In a similar manner the A*-cyclopentenylethylbromide was condensed with diethyl alkyl malonates to give diethyl- A2-cyclopentenylethyl alkyl malonates. A2-CyclopentenylAlkyl Acetic Acids and A2-CyclopentenylethylAlkyl Acetic Acids,The malonic esters were saponified with alcoholic potassium hydroxide as previously described and the potassium salt was obtained by evaporation t o dryness. It was then dissolved in water and added to excess of concd. hydrochloric acid. Upon extraction with ether, evaporation of ether and heating for two hours a t 160-165", the monobasic acids were obtained. The yields were in the neighborhood of 90%. Methyl-9-hydroxyhydnocarpate.-A2-Cyclopentenylethyl bromide was converted into the corresponding Grignard in the usual way. This was then condensed with 8aldehydo-octaaoate in the proportion of 1 mole of aldehyde to 1 mole of Grignard reagent as shown by titration.' After working it up in the usual fashion, and after several careful fractional distillations, a constant boiling product was obtained; b. p. 177-179'at 2 mm.; n?, 1.4720; dqo, 0.9874. Anal. Calcd. for Cl&H&: C, 71.91; H, 10.01. Found: C, 72.29; H, 10.70. g-Hydroxy-d,l-Hydnocarpic Acid.-By saponification of the ester with alcoholic potassium hydroxide and working up in the manner described for the malonic acids, a solid acid was obtained which, upon crystallization from acetone, gave a constant m. p. of 62.0-62.8'. Anat. Subs., 0.3688: 13.75 cc. of 0.1 NNaOH. Neut. equiv. Calcd. for C,rHzsOa: 268.2. Found: 268.2.
Summary 1. A series of A2-cyclopentenylethyl alkyl acetic acids has been prepared. Those members containing 16 t o 18 carbon atoms showed a high bactericidal action toward B. Lepyae. 2 . Three of the higher members of the A2-cyclopentenyl alkyl acetic acids have been prepared. acid has been completed. 3. The synthesis of 9-hydroxy-d,l-hydnocarpic URBANA,
ILLINOIS
(a) Pioller with Adams, THISJOURNAL, 48, 1074 (1926); (b) Davies and Adams, THISJOURNAL, 50, 1749 (1928). 6
